Diabetic foot ulcers can take up to 150 days to heal. A biomedical engineering team
wants to reduce it to 21 days.

They’re planning to drop the healing time by amplifying what the body already does
naturally: build layers of new tissue pumped up by nitric oxide. In patients with
diabetes, impaired nitric oxide production lessens the healing power of skin cells,
and the Centers for Disease Control reports that 15 percent of Americans living with
Type 2 diabetes struggle with hard-to-heal foot ulcers. However, simply pumping up
nitric oxide is not necessarily better. The long-term plan of Michigan Technological
University researchers is to create nitric oxide-infused bandages that adjust the
chemical release depending on the cell conditions.

To do that, the researchers first have to figure what’s going on with nitric oxide
in skin cells. Assessing nitric oxide under diabetic and normal conditions in human
dermal fibroblast cells is the focus of the team’s latest paper, published this week
in Medical Sciences (DOI: 10.3390/medsci6040099).

“Nitric oxide is a powerful healing chemical, but it’s not meant to be heavy-handed,”
Frost says. “We’re looking at the profiles of healthy and diabetic cells to find a
more nuanced way to recover wound function.”

Nitric oxide is a chemical naturally produced by the body to support healing.

As a wound heals, three types of skin cells step in. Macrophages are the first responders—and
the most widely studied cells—that arrive within 24 hours of damage. Next, fibroblasts
arrive, which are like the body’s engineers. They help lay down the extracellular
matrix that makes it possible for the next cells, keratinocytes, to do the heavy-lifting
and rebuilding.

“Wound healing is a complex, cell-mediated symphony of events, progressing through
a series of predictable and overlapping stages,” Frost and her team write in their
Medical Sciences paper. When any part of that orchestra is out of tune, the whole process falls flat.
Fibroblasts, which are not as well studied as macrophages in the healing process,
are a key instrument, and past studies have shown their delayed response in patients
with diabetes may be a major factor in slow healing time.

Nitric Oxide vs. Nitrite

That’s where nitric oxide steps in, a kind of chemical metronome to get the process
back into the right rhythm. But the body’s dermal orchestra is not so simple—just
as playing a metronome louder and louder isn’t necessarily going to make a musician’s
timing improve, flooding a wound with nitric oxide isn’t a cure-all.

“The old approach is to add nitric oxide and sit back to see if it works,” Frost says.
“What we’re finding is that it’s not enough to apply and leave; we have to keep tabs
on how much nitric oxide is actually needed.”

A big problem that Frost and her team address is how nitric oxide is measured in the
first place. Current practice substitutes measuring nitrite for nitric oxide—a misleading
switch, Frost says, because nitrite is a byproduct with no time signature. While stable
nitrite is easier to measure, by itself it cannot relay the real-time healing status
like nitric oxide levels can.

So, Frost’s lab built a nitric oxide-measuring device for their study by hand. That
creates a challenge since it means taking measurements is much harder, which limits
the dataset size, but Frost has an agreement with Zysense LLC to streamline the building
process and produce commercial nitric oxide measurement devices that would improve cell
chemistry research.

Next Steps

Collaboration is a key part of the engineering design process. To build a nitric oxide
bandage with personalized healing power, the team plans to work next with the UP Portage
Health System to gather cell samples from local patients. By expanding their cell
samples—and applying the tech to real-world patients—the team will continue to broaden
their database while deepening their knowledge of nitric oxide mechanisms.

In a few years, they plan to have a working bandage prototype, one that leaves off
the clunky nitrite proxies and nitric oxide dumps. Instead, patients dealing with
diabetic foot ulcers will see a light at the end of the tunnel much sooner than half
a year or more—the nitric oxide-releasing bandage could help heal one of health care’s
toughest diseases in less than a month.

Michigan Technological University is a public research university, home to more than
7,000 students from 54 countries. Founded in 1885, the University offers more than
120 undergraduate and graduate degree programs in science and technology, engineering,
forestry, business and economics, health professions, humanities, mathematics, and
social sciences. Our campus in Michigan’s Upper Peninsula overlooks the Keweenaw Waterway
and is just a few miles from Lake Superior.

Diabetes Stats

15 percent or more live with diabetic foot ulcers and these ulcers make them 2.5 times
more likely to die

90-150 days to heal

$176 billion spent in U.S. every year on diabetes

(Statistics from World Health Organization, International Diabetes Federation, “Diabetic
foot ulcers and their recurrence” in New England Journal of Medicine, and “Advanced biological therapies for diabetic foot ulcers” in Archives of Dermatology)

Research Interests

About the Author

Allison Mills

A through and through geek, Allison writes university research stories. She studied
geoscience as an undergrad at Northland College before getting a master's in environmental
science and natural resource journalism at the University of Montana. She moonlights
as a dance instructor, radio fiend, and occasional rock licker.